Cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis exacerbates occlusive and aneurysmal vascular disease by inducing macrophage proteinase and inflammatory cytokine expression. Despite these observations, administration of selective COX-2 inhibitors is associated with an increased frequency of adverse cardiovascular events. This paradoxical effect is not fully understood; however evidence suggests that suppression of COX-2-dependent PGI2 synthesis by endothelium renders the vascular wall more sensitive to thrombotic stimuli. Nonetheless, blocking the pathophysiologic actions of PGE2 remains an important therapeutic goal. The overall hypothesis to be tested in this application is that blocking PGE2 binding to the EP4 prostanoid receptor can inhibit vascular MMP-9 and IL-6 expression, atherosclerotic lesion development and aneurysmal dilation without altering levels of vascular PGI2. In support of this hypothesis, we report that an EP4 antagonist or EP4 knockdown is as effective as COX-2 inhibition in blocking macrophage MMP-9 expression. Moreover, EP4-dependent signaling stimulates macrophage expression of IL-6, which is linked to COX-2 and MMP-9 expression by a positive feedback loop. Also, EP4-dependent signaling stimulates secretion of PGE2 by inducing expression of microsomal PGE synthase-1 and inhibiting expression of the degradative enzyme 15-hydoxyprostaglandin dehydrogenase. Finally, inhibiting PGE2 binding to EP4 has little impact on the generation of thromboprotective PGI2 by macrophages and endothelial cells in vitro. To test the validity of our hypothesis, we propose the following specific aims: [1] Determine the role of EP4- dependent signaling on the regulation of enzymes downstream of COX-2 that regulate PGE2 synthesis and degradation by macrophages; [2] Determine the role of COX-2 and EP4-dependent signaling on the regulation of smooth muscle cell MMP-9 expression; [3] Determine whether blocking PGE2 binding to EP4 attenuates atherosclerotic lesion development in ApoE-/- mice without altering vascular prostanoid profiles; and [4] Determine whether blocking PGE2 binding to EP4 attenuates the development of angiotensin II-induced aneurysms in ApoE-/- mice without altering vascular prostanoid profiles. If successful, these studies will provide the basis for a novel therapeutic strategy to modulate occlusive and aneurysmal disease.